Cerebral cavernous malformations (CCMs) are the most common brain vascular malformations and are detected in the population at a rate of approximately 0.6 per 100,000. Recognized as familial or sporadic cases, CCMs are characterized as single of multi cluster of enlarged capillary-like channels with a single layer of endothelium and without intervening brain parenchyma. There are specific alterations in brain endothelial barrier components that ultimately lead to vascular hyperpermeability, extravasation of red cells and inflammatory response in brain parenchyma. Patients with CCMs may present with seizures, focal deficits, or nonspecific headaches and as most common complication is hemorrhagic stroke. Although significant effort has been made in defining the genes mutations involved in inherited CCMs, the intra- and intercellular pathogenic mechanisms responsible for vascular hyperpermeability are still largely unknown. The proposed study is designed to elucidate critical molecular events in maintaining the integrity of the brain endothelial barrier and how these are altered cerebral cavernous malformation type 3. In particular, the proposal will address the multisequential events involved in organization of the TJ complex. It will highlight how the interaction between signaling molecules, CCM3 protein and an actin cytoskeleton protein, cortactin, affect the organization and stability of brain endothelial tight junctional complex. Specifically, the following objectives will be evaluated: a) the functional and morphological consequence of CCM3 absence on TJ complex/actin cytoskeleton interactions in conditions of CCM3 pathology and b) the role of CCM3-cortactin interaction in establishing stable interactions between ZO-1 and the actin cytoskeleton and ZO-1 and claudin-5. Collectively, these studies will provide new information related to the mechanisms involved in maintaining the brain endothelial barrier that is relevant not only to CCM3 but also to multiple disease states. Hopefully, this will help to elucidate novel therapeutic strategies to restore vascular hyperpermeability.